A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis

Silvia Moretti, Giorgia Renga, Vasilis Oikonomou, Claudia Galosi, Marilena Pariano, Rossana G Iannitti, Monica Borghi, Matteo Puccetti, Marco De Zuani, Carlo E Pucillo, Giuseppe Paolicelli, Teresa Zelante, Jean-Christophe Renauld, Oxana Bereshchenko, Paolo Sportoletti, Vincenzina Lucidi, Maria Chiara Russo, Carla Colombo, Ersilia Fiscarelli, Cornelia Lass-FlörlFabio Majo, Gabriella Ricciotti, Helmut Ellemunter, Luigi Ratclif, Vincenzo Nicola Talesa, Valerio Napolioni, Luigina Romani

Research output: Contribution to journalArticle

Abstract

T helper 9 (Th9) cells contribute to lung inflammation and allergy as sources of interleukin-9 (IL-9). However, the mechanisms by which IL-9/Th9 mediate immunopathology in the lung are unknown. Here we report an IL-9-driven positive feedback loop that reinforces allergic inflammation. We show that IL-9 increases IL-2 production by mast cells, which leads to expansion of CD25+type 2 innate lymphoid cells (ILC2) and subsequent activation of Th9 cells. Blocking IL-9 or inhibiting CD117 (c-Kit) signalling counteracts the pathogenic effect of the described IL-9-mast cell-IL-2 signalling axis. Overproduction of IL-9 is observed in expectorates from cystic fibrosis (CF) patients, and a sex-specific variant of IL-9 is predictive of allergic reactions in female patients. Our results suggest that blocking IL-9 may be a therapeutic strategy to ameliorate inflammation associated with microbial colonization in the lung, and offers a plausible explanation for gender differences in clinical outcomes of patients with CF.

Original languageEnglish
Pages (from-to)14017
JournalNature Communications
Volume8
DOIs
Publication statusPublished - Jan 16 2017

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    Moretti, S., Renga, G., Oikonomou, V., Galosi, C., Pariano, M., Iannitti, R. G., Borghi, M., Puccetti, M., De Zuani, M., Pucillo, C. E., Paolicelli, G., Zelante, T., Renauld, J-C., Bereshchenko, O., Sportoletti, P., Lucidi, V., Russo, M. C., Colombo, C., Fiscarelli, E., ... Romani, L. (2017). A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis. Nature Communications, 8, 14017. https://doi.org/10.1038/ncomms14017